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EP2252369B1 - Appareil pour dégradation sélective d'adipocytes par ultrason - Google Patents

Appareil pour dégradation sélective d'adipocytes par ultrason Download PDF

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Publication number
EP2252369B1
EP2252369B1 EP09705080.1A EP09705080A EP2252369B1 EP 2252369 B1 EP2252369 B1 EP 2252369B1 EP 09705080 A EP09705080 A EP 09705080A EP 2252369 B1 EP2252369 B1 EP 2252369B1
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EP
European Patent Office
Prior art keywords
ultrasound
energy
transverse
applicator
waves
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EP09705080.1A
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German (de)
English (en)
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EP2252369A2 (fr
Inventor
Alexander Britva
Alexander Dverin
Ziv Karni
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Alma Lasers Ltd
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Alma Lasers Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0004—Applications of ultrasound therapy
    • A61N2007/0008—Destruction of fat cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0073—Ultrasound therapy using multiple frequencies

Definitions

  • the present invention relates to a method and an apparatus for treating adipose tissue with mechanical waves having an ultrasound frequency.
  • FIG. 1A is a histological micrograph of adipose tissue before deliver of longitudinal ultrasound waves.
  • FIG. 1B is a micrograph of adipose tissue that has been damaged by longitudinal ultrasound waves. As shown in FIG. 1B , there is no "intact" adipose tissue - a large fraction of the adipocytes and of other cells are separated from the connective tissue (septae).
  • WO 93/16652 discloses an apparatus which comprises a piezoelectric vibrator adapted to generate ultrasonic energy which is transmitted through an output section to a plastics head.
  • the shape of the head may be varied to suit whichever part of a body on which it is to be used.
  • the material and shape of the head is chosen to allow accurate control of frequency and amplitude of the ultrasonic energy.
  • the preferred ultrasonic frequency is in the range of 20-120 KHz.
  • an apparatus for treating biological tissue comprising an ultrasound transducer configured to produce ultrasound energy; and an ultrasound applicator connected to the ultrasound transducer and including an energy delivery surface, characterized in that the applicator is shaped such as to have a first resonance frequency in which the energy delivery surface of the applicator vibrates parallel to the direction of ultrasound propagation through the applicator and a second different resonance frequency in which the energy delivery surface of the applicator vibrates in the plane normal to the direction of ultrasound propagation through the applicator, and the apparatus has a longitudinal mode of operation in which the ultrasound transducer excites the applicator at said first frequency and a transverse mode of operation in which the ultrasound transducer excites the applicator at said second frequency.
  • ultrasound energy emitted by the energy delivery surface when operating in the transverse mode propagates in directions that are mutually inclined, whereby ultrasound energy of the transverse ultrasound waves is incident from multiple directions on points lying in the path of the ultrasound energy emitted by the applicator.
  • the energy delivery surface of the applicator may have surface properties such that the delivered ultrasound waves have the following properties:
  • the delivery surface may be a convex surface having positioned thereon at least one of multiple discontinuous surfaces, a plurality of protrusions, a plurality of indentations, a plurality of vertical ridges, and a plurality of concentric circular ridges.
  • the applicator may suitably include a proximal portion operatively coupled to the ultrasound transducer, a distal portion defining the energy delivery surface, and an elongated neck portion connecting the proximal portion to the distal portion, the applicator being dimensioned such that:
  • the apparatus may further comprise a controller operative to cause the applicator and the ultrasound transducer to:
  • the apparatus of the invention is designed to selectively damage adipose tissue beneath the surface of the skin by delivering transverse ultrasound waves to the adipose tissue via the skin surface.
  • the "deeply-penetrating" transverse ultrasound waves propagate or conduct to the fibers/membrane structure (or tissue matrix) of adipose tissue to (i) deform and damage adipocytes cell membranes by repeatedly stretching and allowing to relax the cell membranes while (ii) causing substantially no collateral damage to surrounding tissue.
  • Histological results have indicated that immediately after application of the ultrasound waves (for example, within an half-hour), it is possible to observe at least some adipocytes that (i) have not been ruptured and are part of an intact tissue matrix but (ii) whose cell membranes have, nevertheless, been deformed - for example, having a "zig-zag" shape. Furthermore, histological results have also indicated that at a later time (for example, after one or several days) at least these adipocytes (i.e., whose cell membranes have been damaged) are later removed from the adipose tissue and the contents (for example, triglycerides) of these adipocytes have been released.
  • the administered transverse ultrasound energy induces observable adipocyte cell membrane deformation within a relatively short period of time (e.g., within about 30 min. of treatment) and (ii) is effective to trigger a biological process acting over a relatively long period of time (e.g., a few days) whereby (a) the damaged adipocytes disappear and (b) the triglycerides contained in the damaged adipocytes are slowly removed by natural metabolic and healing processes that occur over this longer period of time.
  • a relatively short period of time e.g., within about 30 min. of treatment
  • a biological process acting over a relatively long period of time e.g., a few days
  • the ultrasound-based apparatus disclosed herein advantageously provides a relatively "gentle" treatment employing transverse ultrasound waves where there is no requirement to mechanically rupture most adipocytes within a region of tissue at the time of treatment, but where the adipocytes are damaged by the ultrasound energy to a sufficient extent to induce their subsequent elimination by natural processes.
  • the delivered transverse ultrasound energy is 'scattered' within the treated tissue so that ultrasound energy is delivered in multiple directions at a given time rather than delivered in a single direction and/or focused to a single location. This is useful for achieving a higher success rate whereby more adipocytes within a given volume of adipose tissue are successfully damaged by the relatively low energy transverse ultrasound wave to the extent required for their eventual destruction, (without relying exclusively upon "thermal effects").
  • This scattering of delivered energy may be provided at least in part by shape and/or surface features (and/or other features) of a convex energy-delivery surface of the ultrasound applicator or sonotrode.
  • the terms “applicator” and “sonotrode” are used interchangeably herein.
  • transverse ultrasound waves are provided in combination with longitudinal ultrasound waves that heat the upper layers of tissue.
  • Some embodiments of the present invention provide an ultrasound device including a 'mushroom-shaped' sonotrode configured to deliver both transverse ultrasound energy as well as longitudinal ultrasound energy from a single device.
  • Embodiments of the present invention provide an apparatus (for example, see FIG. 4 ) and method for selectively damaging adipose tissue below the skin surface by delivering transverse mechanical waves of an ultrasound frequency using a sonotrode (for example, see element 140 of FIG. 4 ) having a convex energy delivery surface 180 in contact with the skin surface.
  • a sonotrode for example, see element 140 of FIG. 4
  • the delivered transverse ultrasound waves (i) induce mechanical motion within the adipose tissue in a direction that is perpendicular to the wave propagation direction; (ii) selectively propagate through the fibers/membrane matrix of the adipose tissue without substantially penetrating into the liquid fraction of adipose tissue (or other biological tissue); and (iii) irreversibly damage adipocytes by deforming the adipocytes' cell membranes.
  • the relatively "low energy" delivered transverse ultrasound waves are useful for selectively damaging adipocytes while causing little or no damage to other structures in the biological tissue.
  • the delivered transverse ultrasound waves which propagate within the fibers/membrane matrix of the biological tissue repeatedly stretch cell membranes of different types of cells, including but not limited to adipocytes.
  • the repeated stretching of adipocyte membranes deforms the adipocytes membranes and triggers delayed cell death of the adipocytes without substantially triggering cell death of other types of cells.
  • the delivered transverse ultrasound energy may selectively damage the adipose tissue while causing substantially no collateral damage to other tissues (e.g., blood vessels, connective tissue, dermis, etc) (see FIG. 5D which illustrates intact nerve and blood vessels surrounded by damaged fat tissue).
  • tissues e.g., blood vessels, connective tissue, dermis, etc
  • the delivered transverse ultrasound energy may injure or damage at least some adipocytes within adipose tissue below the dermis without immediately rupturing them and without destroying the adipose tissue matrix in which these damaged adipocytes reside (see, e.g., see FIG. 5B ), and (ii) after a certain period of time (for example, one or more days), the damaged adipocytes are broken down and removed from the adipose tissue (see, e.g., FIG. 5C ).
  • the transverse mechanical waves of an ultrasound frequency are delivered using a mushroom shaped applicator or sonotrode (see for example, FIGS. 7A-7B ) having a contactable "energy delivery surface” that is induced to vibrate in a "transverse wave mode.” (i.e., substantially perpendicular to the longitudinal axis 164) (one theoretical model describing behavior of the sonotrode is presented with reference to FIGS. 9A-9C ).
  • this energy delivery surface 180 is coupled to the skin of the biological tissue (i.e., brought into direct contact or indirect contact), "deep penetrating" transverse mechanical waves are delivered into the biological tissue to the adipose tissue.
  • the delivered transverse mechanical waves are relatively low energy mechanical waves that induce little or no cavitation in the biological tissue and do not significantly damage cells of the "higher tissue layers" (i.e., layers between the adipose tissue and the surface of the skin) through which they pass en route to the adipose tissue. Therefore, the transverse mechanical waves may be said to specifically target the adipose tissue.
  • FIGS. 12 and 13A where the propagation axes are labeled by element 270 and where scattering may be provided by sonotrode geometry and/or surface properties of the energy delivery surface 180 via which ultrasound waves are delivered.
  • FIGS. 12-13A at least some axes 270 of propagation of transverse mechanical waves of ultrasound frequency propagating within the biological tissue are not parallel to each other.
  • the energy delivery surface 180 is shaped so that it includes multiple discontinuous surfaces and/or a plurality of protrusions (see for example, concentric ridges 182 and/or indentations/depressions. This may be useful for facilitating the "scattering" of the transverse mechanical waves into the tissue (for example, compare FIGS. 12 and 13A ).
  • the targeted adipocytes are non-spherical and are not necessarily oriented in the same orientation (see, for example, element 292 of FIG. 11B ).
  • the preheating is provided using RF energy (see, for example, FIG. 19 ).
  • the preheating is carried out by delivering longitudinal ultrasound waves to the biological tissue, for example, via the same energy delivery surface 180 used for delivering transverse mechanical waves of ultrasound frequency.
  • the "mushroom-shaped" sonotrode 140 of FIG. 4 and 7A is assembled with an ultrasound transducer 130 operatively coupled to the proximal portion of the sonotrode (e.g., attached to and/or located on the proximal portion 150).
  • distal portion 170 of the sonotrode may behave as a resonator having at least two vibration modes.
  • a first "bending" mode associated with a first “driving” frequency of the ultrasound transducer
  • a transverse standing wave of ultrasound frequency is generated within distal portion 170 (for example, see FIGS. 8 , 9A-9C and 17A ).
  • Engaging sonotrode 140 to a skin surface when in this first mode (also called the "cold" mode or "traverse wave” mode) is useful for inducing transverse mechanical waves in the biological tissue beneath the skin.
  • a longitudinal standing wave of ultrasound frequency is generated within distal portion 170 (for example, see FIGS. 16 and 17B ).
  • Coupling sonotrode 140 to a skin surface when in the second or “hot” mode is useful for inducing longitudinal mechanical waves (i.e., longitudinal ultrasound waves) in the biological tissue beneath the skin.
  • the longitudinal ultrasound waves are useful for preheating the upper layers of biological tissue.
  • FIG. 15A illustrates exemplary resonance frequencies for one particular non-limiting ultrasound applicator or sonotrode (e.g., 140 of FIG. 7A ).
  • the x-axis of the graph of FIG. 15A is the operating frequency, and the y-axis is the acoustic power in the transducer and the sonotrode.
  • the transverse ultrasound waves are deeper-penetrating than the longitudinal ultrasound waves, and have a lower rate of absorption.
  • longitudinal waves are generally transmitted through the liquids of the tissue and may generate cavitation in the upper layers of tissue and (ii) transverse waves pass through the upper layers, are absorbed mostly by the fiber matrix of the deeper adipose tissue, and do not generate cavitation.
  • the longitudinal waves are better absorbed by the upper layer of tissues, they do not penetrate as deeply (as is shown in FIG. 14 ), and hence, are useful for heating the upper layers of tissue.
  • hybrid treatment protocols include a first "preliminary” treatment phase where the mechanical waves of an ultrasound frequency are primarily longitudinal ultrasound waves and a second "main” treatment phase where the mechanical waves of an ultrasound frequency are primarily transverse waves are disclosed herein (see, for example, FIGS. 18 and 19 and the accompanying discussion).
  • the multimode ultrasound device i.e., an ultrasound device capable of operating in both a "cold mode” and “hot mode” as described herein
  • includes an electronic controller see element 120 of FIG. 4 ) that is programmed to provide one or more presently-disclosed protocols.
  • the mechanical waves are of a low ultrasound frequency-for example, below 100 kHz, or below 80 kHz.
  • ultrasound waves refers to mechanical waves of an ultrasound frequency- i.e. at least 20 kHz.
  • ultrasound waves may refer either to (i) longitudinal mechanical waves of ultrasound frequency; or (ii) transverse mechanical waves of ultrasound frequency.
  • ultrasound waves and “mechanical waves of an ultrasound frequency” are used interchangeably herein.
  • ultrasound vibrations refers to any mechanical vibrations of an ultrasound frequency.
  • ultrasound vibrations and “mechanical vibrations of an ultrasound frequency” are used interchangeably herein.
  • the presently-disclosed teachings may be used to treat adipocytes in any location of the body, including but not limited to the abdomen region, the buttocks and the thighs.
  • Some of the herein disclosed embodiments relate to a technique and device for "selectively" damaging adipocytes using ultrasound energy - i.e., damaging of adipocytes while causing little or no damage to proximate tissues (e.g., blood vessels, connective tissue, dermis, nerve tissue, etc). There is no requirement of selectively targeting certain "targeted adipocytes" more than other "non-targeted adipocytes.”
  • the sonotrode 140 and/or ultrasound transducer 130 and/or controller 120 are “configured” or “operative” to provide a certain feature of delivered ultrasound waves (or a feature of ultrasound vibrations within or on the sonotrode or a portion thereof, or a certain "momentum” feature of the sonotrode), this means that any suitable set of device parameters familiar to one skilled in the art may be used. In different non-limiting examples, these device parameters may relate to sonotrode geometry and/or sonotrode material properties and/or 'surface properties' of an energy delivery surface of the sonotrode 140 and/or ultrasound transducer power levels and/or ultrasound frequency and/or one or more pulse parameters and/or any other structural parameter familiar to the skilled artisan. It will be appreciated that the above list is intended as exemplary and not as limiting.
  • the feature(s) of the delivered ultrasound may be defined in any appropriate manner - for example, in terms of fraction of total ultrasound energy that is energy of longitudinal and/or transverse ultrasound waves, direction(s) of wave propagation, in terms of the effect that the delivered ultrasound has upon biological tissue subjected to the delivered ultrasound or in any other manner recognizable to the skilled artisan.
  • FIGS. 2-3 Apparatus 100 Associated with Handpiece 90
  • FIG. 2 is a schematic, pictorial illustration of an apparatus 100 for treating adipose tissue with ultrasound energy, in accordance with an embodiment of the present invention. As illustrated in FIG. 2 , at least a portion of apparatus 100 is mechanically integrated with handpiece 90.
  • operator 60 such as a physician, operates apparatus 100.
  • operator 60 may (i) couple ultrasound sonotrode 140 of handpiece 90 to the skin of a patient 50 and (ii) move the sonotrode 140 over the skin of the patient using handpiece 90.
  • a control console 70 supplies electrical energy to device 90 via a cable 80.
  • FIG. 3 is a schematic, cutaway view of handpiece 90, in accordance with some embodiments. Electrical current carried by cable 80 is fed to ultrasound transducer 130, which provides ultrasound energy to sonotrode 140. Further details are presented hereinbelow.
  • FIG. 4 is an illustration of an apparatus 100 for delivering ultrasound energy to biological tissue 200 according to some embodiments.
  • the apparatus 100 includes: (i) an ultrasound transducer 130 (for example, a piezo-ceramic transducer or a magnetostrictive-type ultrasound transducer or a transducer of any other type) for producing ultrasound energy at one or more frequencies; and (ii) a sonotrode 140 or ultrasound applicator 140 configured to deliver ultrasound energy (i.e., transverse mechanical waves of an ultrasound frequency and optionally longitudinal ultrasound waves) provided by ultrasound transducer 130 to the biological tissue 200 via an energy delivery surface 180 in contact with biological tissue 200.
  • ultrasound energy i.e., transverse mechanical waves of an ultrasound frequency and optionally longitudinal ultrasound waves
  • sonotrode 140 is a mushroom-shaped ultrasound applicator including a proximal portion 150 connected to a distal portion 170 via neck portion 160.
  • sonotrode 140 is configured so that distal portion 170 behaves as a resonator.
  • transducer 130 produces ultrasound energy at one of the "driving frequencies," it induces transverse mechanical vibrations in the distal portion 170 in a direction that is substantially perpendicular to longitudinal axis 164.
  • apparatus 100 is a multi-mode device that is configured, (i) to deliver primarily transverse ultrasound energy to biological tissue 200 when in a first, cold mode, and (ii) to deliver primarily longitudinal transverse energy to biological tissue 200 when in a second, hot mode.
  • the second mode or 'hot mode' is useful for heating at least a portion of the biological tissue (for example, upper layers of tissue), while in the first mode or 'cold mode,' the biological tissue may not be heated at all and/or heated only minimally.
  • the delivered transverse mechanical waves of ultrasound frequency travel to the adipocytes 240 of adipose tissue 230 via epidermis 210 and dermis 220, causing no, or only relatively minimal, collateral damage to the layers of tissue above the adipose tissue 230.
  • energy delivery surface 180 of sonotrode 140 is a substantially convex surface (e.g., having a hemispherical shape). As discussed below with reference to FIGS. 8-9C , this may be useful for scattering incident ultrasound waves at different angles within the treated biological tissue.
  • a 'dynamic' or 'in-motion' treatment technique is applied, whereby ultrasound applicator 140 is moved transversally over the surface of biological tissue 200 (for example, at a minimal speed of 0.5 cm/sec or 1 cm/sec or 2 cm/sec or 3 cm/sec for a minimum distance that is at least 5 cm or 10 cm or 15 cm) as transverse and/or longitudinal ultrasound waves are delivered to biological tissue 200.
  • the movement of the applicator 140 over the treated tissue may be useful for improving energy coupling such as by generating a pressure between the applicator 140 (i.e., energy delivery surface 180) and the tissue. This may provide a better ultrasound coupling, and is useful for facilitating and ensuring treatment of the entire region sought to be treated.
  • some sort of petroleum jelly may be applied to energy delivery surface 180. This may be useful for reducing dynamic friction between energy delivery surface 180 and the upper surface of biological tissue 200. Furthermore, as discussed below, in some embodiments it is desirable to improve acoustic coupling between applicator 140 and biological tissue 200 (i.e., to reduce the amount of reflected power), and Vaseline may be useful for this purpose as well.
  • petroleum jelly fills up the voids between the applied sonotrode surface and biological tissue, "replacing" the air, and improving acoustic impedance matching of the system. This may decrease the fraction of ultrasonic power that is reflected.
  • the apparatus 100 of FIG. 4 may also include (i) a reflector 144 for reflecting generated ultrasound energy downwards (the reflector is usual part of ultrasonic transducer) towards the biological tissue 200; (ii) a current source 110 for powering transducer 130 and (iii) a device controller 120 for modulating the electrical power delivered to transducer 130 (for example, for controlling the amplitude and/or frequency of transducer 130 and/or for controlling one or more pulse parameters in the event that transducer 130 generates pulsed ultrasound energy).
  • a reflector 144 for reflecting generated ultrasound energy downwards (the reflector is usual part of ultrasonic transducer) towards the biological tissue 200
  • a current source 110 for powering transducer 130
  • a device controller 120 for modulating the electrical power delivered to transducer 130 (for example, for controlling the amplitude and/or frequency of transducer 130 and/or for controlling one or more pulse parameters in the event that transducer 130 generates pulsed ultrasound energy).
  • the apparatus 100 also includes a mechanism for epidermal cooling to minimize or eliminate pain.
  • device controller 120 may be implemented in any combination of electrical circuitry and executable code modules. In some embodiments, device controller 120 may include one or more elements depicted in FIG. 21 .
  • current source 110 and controller 120 are drawn in close proximity of sonotrode 140 in FIG. 4 , this is not a requirement. In some embodiments, current source 110 and/or controller 120 are attached to and/or associated with console 70 (see FIG. 2 ).
  • one or more features are provided to facilitate matching of acoustic impedances between applicator 140 and biological tissue 200.
  • sonotrode 140 may be constructed of any material, in some embodiments, materials having relatively lower acoustic impedance (i.e., that are relatively close to the 2-2.5 MRayls acoustic impedance of biological tissue) are chosen. Thus, in some embodiments, applicator or sonotrode 140 is constructed primarily or exclusively of aluminum (or an alloy thereof) having an acoustic impedance of about 17 MRayls rather than titanium, which has an acoustic impedance of about 27 MRayls. Alternatively or additionally, plastic materials (for example, having an acoustic impedance that is greater than the acoustic impedance of biological tissue but less than the acoustic impedance of aluminum) may be used.
  • the acoustic impedance of sonotrode 140 should not be too low, since, in certain some embodiments, the acoustic impedance of ceramic of transducer 130 may be about 40 MRayls.
  • sonotrode 140 (or a portion thereof - for example, proximal, neck or distal portions) may have an acoustic impedance of at least 5 MRayls or at least 7.5 MRayls or at least 2 or 3 times an acoustic impedance of biological tissue).
  • a material having an intermediate acoustic impedance for example, a petroleum jelly such as Vaseline® that is greater than the acoustic impedance of biological tissue but less than the acoustic impedance of the applicator is applied to energy delivery surface 180.
  • energy delivery surface 180 may be coated with a substance (for example, a plastic or Teflon®, or alumina) useful for facilitating matching of acoustic impedance.
  • a substance for example, a plastic or Teflon®, or alumina
  • sonotrode 140 is constructed of aluminum with an alumina coating.
  • sonotrode 140 of a relatively "rigid” material that is less likely to absorb ultrasound vibrations in the form of heat.
  • sonotrode 140 (or proximal and/or neck and/or distal portion) is constructed primarily of a material which is relatively "rigid” - for example, (i) a material having a tensile strength that is at least about 10,000 or 15,000 or 20,000 or 25,000 or 30,0000 or 40,000 or 50,000 psi (which is at least about 70 or 105 or 140 or 175 or 210 or 245 or 280 MPa) and/or (ii) a material having a shear strength that is at least about 15,000 or 20,000 or 25,000 or 30,000 or 40,000 or 50,000 psi (which is at least about 105 or 140 or 175 or 210 or 280 or 350 MPa).
  • sonotrode 140 in order reduce the likelihood of a "mechanical softening" of sonotrode 140, sonotrode 140 (or proximal and/or neck and/or distal portion) is constructed primarily of a material having a relatively "high" melting point - for example, at least 300 degrees Celsius or at least 400 degrees Celsius or at least 500 degrees Celsius.
  • sonotrode 140 in order to facilitate cooling of sonotrode 140 (for example, using cold water), it is desirable to construct sonotrode 140 of a relatively thermally conductive material.
  • sonotrode 140 (or proximal and/or neck and/or distal portion) is constructed primarily of a material with a relatively "large" thermally conductivity - for example, at least 5 W m -1 K -1 or at least 10 W m -1 K -1 or at least 20 W m -1 K -1 or at least 50 W m -1 K -1 or at least 100 W m -1 K -1 or at least 200 W m -1 K -1 .
  • proximal 150, neck 160 and distal 170 portions of sonotrode 140 are 'integrally formed' with each other, as opposed to glued together or fastened together.
  • FIGS. 5A-5C Histological Results Related Treating Adipose Tissue with Transverse Ultrasound Waves
  • FIGS. 5A-5C are micrographs of subcutaneous adipose tissue: (i) before ultrasound damage (see FIG. 5A ); (ii) immediately after ultrasound damage by transverse ultrasound mechanical waves (i.e., within 30 minutes; see FIG. 5B ); and (iii) three days after the ultrasound damage by transverse ultrasound mechanical waves (see FIG. 5C ).
  • the stretching and/or compressing of cell membranes by the transverse mechanical waves of ultrasound frequency causes a "zig-zag" pattern that (i) introduces undulating membrane geometry (see, for example, the portions of cell membranes within the white ovals) to cell membranes of the adipocytes and (ii) increases the surface area of the cell membranes (see also FIGS. 25A-25B ).
  • FIG. 5B Although the adipocytes in FIG. 5B have been damaged by the transverse mechanical waves of ultrasound frequency, the cells are not ruptured but alive at the time immediately after (i.e., less than 30 minutes after) administration of the transverse mechanical waves. Furthermore, in contrast to the situation in FIG. 1B where there is extensive damage of both adipocytes and other structures caused by longitudinal ultrasound waves, the damage in the example of FIG. 5B appears to be substantially confined to adipocytes only, thereby providing selective treatment.
  • the adipocyte cell membrane deformation damage by the ultrasound energy is effective for triggering a delayed cell death process whereby the adipocytes are eventually (e.g., within 3 days) broken down by biological pathways, as evidenced in FIG. 5C .
  • adipocytes are removed over hours or days rather than instantly ruptured, it may be possible to facilitate metabolism and eventual excretion of the fatty liquid content of the adipocytes.
  • adipocytes that are damaged but not ruptured does not imply absolutely no cells will be immediately ruptured when the adipose tissue is subjected to mechanical waves of ultrasound frequency.
  • a small number e.g., less than 50% but generally less than about 20%
  • adipocytes within the adipocyte tissue may also be immediately ruptured by the applied ultrasound energy.
  • FIGS. 6A-6B - A Flowchart of a Technique for Treating Adipose Tissue with Transverse Ultrasound Waves
  • FIG. 6A is a flow chart of a technique for treating adipose tissue with transverse mechanical waves of ultrasound frequency.
  • the transverse mechanical waves of ultrasound frequency are delivered to adipose tissue beneath the dermis - for example, using a sonotrode 140 such as or similar to the sonotrode depicted in FIGS. 4 , 7A-7B.
  • the mechanical waves of ultrasound frequency are delivered such that in step S515 the cell membranes of the adipocytes are repeatedly stretched to damage the adipocytes by deformation without immediately rupturing a most of the damaged adipocytes (for example, see FIG. 5A ).
  • the mechanical waves of ultrasound frequency are delivered to trigger a biological process so that in step S519, "delayed death" of the adipocytes is triggered.
  • FIG. 6B is a flow chart of an exemplary implementation of step S511 according to some embodiments.
  • step S535 at a time that energy delivery surface 180 of sonotrode 140 is in contact with a patient's skin, the energy delivery surface mechanically vibrates in a direction that is substantially parallel to a local plane of energy delivery surface (for example, see FIGS. 9A-9C )
  • FIG. 7A-7C are to-scale illustrations of "mushroom-shaped" ultrasound applicator or sonotrode 140.
  • sonotrode 140 is symmetric about longitudinal axis 164, though this is not a limitation; a sonotrode according to the invention may be asymmetric about the longitudinal axis 164.
  • Sonotrode 140 includes: (i) proximal portion 150, (ii) distal portion 170 and (iii) an elongated neck portion 160 defining an elongated neck axis.
  • sonotrode 140 is substantially axisymmetric, so the elongate neck axis coincides with longitudinal axis 164, though this is not a limitation,
  • Sonotrode 140 also includes or is operatively coupled to an ultrasound transducer 130.
  • ultrasound transducer 130 may be attached to a proximal portion 150, although other configurations are contemplated (for example, where ultrasound transducer 130 is placed on a surface of proximal portion 150, such as the surface opposite the neck portion of the sonotrode).
  • sonotrode 140 is constructed, for example, as a solid and/or hollow form such that when ultrasound transducer 130 generates longitudinal mechanical waves of a particular driving ultrasound frequency within proximal portion 150, energy of these longitudinal waves travels into neck portion 160 and induces distal portion 170 to vibrate at an ultrasound frequency in a direction that is substantially perpendicular to the longitudinal direction of the sonotrode (i.e., a direction parallel to longitudinal axis 164).
  • ultrasound transducer 130 may induce a standing wave in distal portion 170 in a direction that is substantially perpendicular (e.g., within a tolerance of 25, 20, 10, or 5 degrees) to longitudinal axis 164.
  • sonotrode 140 is operative to "convert" plunger-type vibrations in proximal portion 150 and neck portion 160 into bending-type (or transverse) vibrations in distal portion 170.
  • sonotrode 140 is dimensioned so that: (i) the ratio between dimension B of the neck portion 160 parallel to the elongate axis of the neck and dimension d1 of the neck portion 160 perpendicular to the elongate axis of the neck is at least 1.5 (or at least 2 or at least 2.5); (ii) the ratio between a dimension d2 of the distal portion 170 perpendicular to the elongate axis of the neck and dimension C of the distal portion 170 parallel to the elongate axis of the neck is at least 2 (or at least 2.5 or at least 3); (iii) the ratio between dimension D of the proximal portion 150 perpendicular to the elongate axis of the neck and dimension d1 of the neck portion 160 perpendicular to the elongate axis of the neck is at least 2.5 (or at least 3 or at least 3.5); (iv) the ratio between dimension d2 of the distal portion 1
  • the wavelength ⁇ of the mechanical wave of an ultrasound frequency may be as follows: ⁇ longitudinal (mm) ⁇ transverse (mm) Aluminum 105 43 Stainless steel 95 44 Saline, salted water and lymph 24 - Fibers (collagen) approx 39 14
  • the figure is labeled as "cold mode" because, in some embodiments, when the vibrations in the distal portion are substantially perpendicular to the longitudinal axis 164, mechanical energy that is primarily in the form of transverse mechanical waves of ultrasound frequency is delivered to the biological tissue in a manner that does not substantially heat the biological tissue.
  • transducer 130 in order to achieve the "cold mode” effect described in FIG. 7A , transducer 130 needs to generate ultrasound at a special “driving frequency” or “resonant frequency.”
  • the ultrasound waves generated by transducer 130 are at driving frequency different from the cold mode driving frequency.
  • the vibrations instead of mechanical vibrations being induced in a direction substantially perpendicular to the elongate axis of neck 160 and to longitudinal axis 164 in the distal portion 170 "resonator," the vibrations are induced in a direction parallel to those axes. These vibrations are useful for delivering a longitudinal wave to biological tissue 200, thereby heating the biological tissue (thus FIG. 7B is labeled "hot mode"). When present, cavitation formation within the biological tissue may facilitate this heating.
  • apparatus 100 when apparatus 100 is in "cold mode" or "transverse wave mode” (see FIG. 7A ) then: (i) at least a minimum percentage (e.g., at least 30% or at least 50% or at least 70% or at least 90%) of ultrasound vibration energy within distal portion 170 is transverse ultrasound vibrations that are substantially perpendicular to the elongate axis of neck portion 160 and/or longitudinal axis 164; and/or (ii) at least a minimum percentage (i.e., at least 30% or at least 50% or at least 70% or at least 90%) of ultrasound wave energy delivered via energy delivery surface 180 are transverse ultrasound waves.
  • a minimum percentage e.g., at least 30% or at least 50% or at least 70% or at least 90%
  • At least a minimum percentage e.g., at least 30% or at least 50% or at least 70% or at least 90%
  • at least a minimum percentage e.g., at least 30% or at least 50% or at least 70% or at least 90%
  • at least a minimum percentage e.g., at least 30% or at least 50% or at least 70% or at least 90%
  • FIG. 7A relates to the direction of ultrasound vibrations at transducer 130. It is noted that although the ultrasound vibrations within the distal portion 170 may be primarily vibrations in a direction substantially perpendicular to the elongate axis of neck portion 160 and/or substantially perpendicular to central longitudinal axis 164 (within a tolerance of 30 degrees or 20 degrees or 10 degrees), the generated vibrations at transducer 130 (and/or within the proximal portion and/or within neck portion) are primarily (i.e., at least 50% but may also be at least 70% or at least 90% by energy) in a direction that is substantially parallel to an elongate axis of neck portion 160 and/or substantially parallel to longitudinal axis 164 (within a tolerance of 30 degrees or 20 degrees or 10 degrees.).
  • the generated vibrations at transducer 130 may be primarily (i.e., at least 50% but may also be at least 70% or at least 90% by energy) in a direction that is substantially perpendicular (within a tolerance of 30 degrees or 20 degrees or 10 degrees.) to a local plane of the skin in contact with energy delivery surface 180.
  • the ultrasound vibrations may be generated by an elongated transducer 130 whose elongate axis is substantially parallel (within a tolerance of 30 degrees or 20 degrees or 10 degrees) to a surface of the skin in contact with energy delivery surface 180.
  • the elongate axis of transducer 130 is substantially perpendicular (i.e., within a tolerance of 30 degrees or 20 degrees or 10 degrees) to an elongate axis of neck portion 160 and/or substantially perpendicular (i.e., within a tolerance of 30 degrees or 20 degrees or 10 degrees) to longitudinal axis 164.
  • ultrasound vibrations may be generated within sonotrode 140 so that a plurality of nodes 142 and anti-nodes 144 are produced. At the positions of the nodes 142 there may be a local maximum in ultrasound vibration intensity, and at the positions of the antinodes 144 there is a local minimum.
  • node DIST the distance between adjacent nodes or antinodes is node DIST . It is noted that there is no requirement that node DIST remain the same in both modes - in fact, in many embodiments, node DIST is different for each mode.
  • the distance between adjacent nodes or antinodes may depend on the prevailing mode - i.e. when in 'cold' mode where a majority of the ultrasound energy delivered from energy delivery surface 180 is energy of traverse ultrasound waves, node DIST adopts a first value ( node DIST ) traverse , and when in 'hot' mode where a majority of the ultrasound energy delivered from energy delivery surface 180 is energy of longitudinal ultrasound waves, node DIST adopts a second value ( node DIST ) longitudinal .
  • FIGS. 7A-7C Ultrasound Energy intensity as a Function of Location on Energy Delivery Surface 180
  • the intensity of the ultrasound is greater at the "boundary" of energy-delivery surface, and lesser near the "center” (for example, where longitudinal axis 164 intersects energy delivery surface 180).
  • the sonotrode includes an energy delivery surface 180 for delivering energy of the induced ultrasound vibrations to the patient's skin; and ii) when the transducer 130 is in operation, the energy flux is at most 30% of the maximum energy flux on the energy on the energy delivery surface 180 at a point on the energy delivery surface 180 where the elongate axis of the neck intersects the energy delivery surface 180.
  • FIG. 8 is a flow chart of an exemplary routine for generating mechanical vibrations in the energy delivery surface 180 of the applicator/sonotrode 140 that are substantially parallel to a local plane of the energy delivery surface and/or substantially perpendicular to an elongate axis of neck portion 160 (which may coincide with longitudinal axis 164).
  • ultrasound waves having a first driving frequency for example, a cold mode resonant frequency illustrated in FIG. 15A
  • a first driving frequency for example, a cold mode resonant frequency illustrated in FIG. 15A
  • These ultrasound waves propagate downwards (i.e., in a direction towards the distal portion 170) and enter the neck portion 160 in step S315.
  • the longitudinal waves drive or induce within distal portion 170 a transverse standing wave on energy delivery surface 180. It is this transverse standing wave that, in turn, induces traveling transverse waves in biological tissue 200 during treatment.
  • FIGS. 9A-9C Pinching and Pulling Motion
  • FIG. 9A-9C describe one theoretical model of how sonotrode 140 behaves when in "cold mode.”
  • FIG. 9A illustrates the standing transverse mechanical wave on the energy delivery surface.
  • Energy delivery surface 180 functions as a "vibrating skin surface" which is driven by the ultrasound vibrations generated by ultrasound transducer 130.
  • intersection location 166 is at the center of the energy delivery surface.
  • FIGS. 9B-9C Reference is now made to FIGS. 9B-9C .
  • FIGS. 9A-9C there is a single stationary point 166 in cold mode that does not vibrate in a transverse direction. In other examples, there may be multiple stationary points 166, depending on the vibration modes.
  • the net momentum of matter of sonotrode 140 and/or of distal portion 170 in a plane P that is perpendicular to an elongate axis of neck 160 may be substantially zero because of the 'pinching/pulling".
  • momentum at certain subsections in the plane P may be non-zero
  • the net-momentum of matter within plane P of matter of sonotrode 140 at a time of transverse ultrasound vibrations may, nevertheless, be substantially zero due to these cancellation effects.
  • d V is a differential volume element.
  • This may be normalized, and it may be possible, in some embodiments, to write: ⁇ SONOTRODE ⁇ ⁇ ⁇ v P ⁇ dV 2 ⁇ SONOTRODE ⁇ ⁇ dV ⁇ ⁇ SONOTRODE ⁇ ⁇ ⁇ v P 2 ⁇ dV ⁇ fraction , or ⁇ DISTAL_PORTIO ⁇ ⁇ ⁇ v P ⁇ dV 2 ⁇ DISTAL_PORTIO ⁇ ⁇ dV ⁇ ⁇ DISTAL_PORTION ⁇ ⁇ ⁇ v P 2 ⁇ dV ⁇ fraction .
  • the fraction may be equal to 0.3 or 0.2 or 0.1 or 0.05 or 0.01 or 0.005.
  • any of these conditions above may prevail for at least 1 second or at least 3 seconds or at least 5 seconds.
  • FIGS. 10-13C Treatment of a Plurality of Adipocytes
  • FIG. 10 illustrates a plurality of adipocytes 240 within a control volume 280.
  • control volume 280 for example, at least 10,000 or at least 30,000 or at least 50,000 or at least 70,000 adipocytes within 1 cm 3 ), and not every single adipocyte will be sufficiently damaged to trigger delayed death.
  • control volume 280 for example, a rectangular prism whose length, width, and depth are at least 1 cm, and which is "buried" beneath the dermis (e.g., at least 1 cm beneath the surface) so the distance between the nearest surface of the control volume 280 and the outer skin surface, d, is greater than or equal to 1 cm).
  • the mechanical waves of an ultrasound frequency are delivered in a manner so as to (i) trigger delayed cell death within 3 days of a majority of adipocytes (or a substantial majority of at least 70% or at least 90%) residing within a rectangular prism control volume 280 of adipose tissue beneath the dermis (ii) without rupturing, within 30 minutes, any more than 2% (or any more than 5% or any more than 10% or any more than 20%) adipocytes 240 residing within the control volume 280.
  • Control volume 280 of adipose tissue (i) has a given thickness, length and width; (ii) has a given volume V equal to the product of the thickness, length and width (units of V are cubic centimeters); (iii) is located beneath the skin dermis; and (iv) includes at least a number X adipocytes, where X is the product of the volume V of control volume 280 in cubic centimeters and a number of adipocytes per cm 3 which is at least 10,000 cells or at least 30,000 cells or at least 50,000 cells.
  • the size of V may be 1 cm 3 , or 2 cm 3 , or 4 cm 3 or 10 cm 3 .
  • control volume 280 is 1 cm, and the length and width are each 2 cm.
  • FIG. 11A illustrates damage to an adipocyte membrane 244 by an incident transverse mechanical wave of ultrasound frequency having a propagation axis that is labeled as 270.
  • the extent of damage caused by the transverse mechanical wave of ultrasound frequency may depend upon an "orientation" of a non-spherical adipocyte relative to a propagation axis 270 of an incoming transverse mechanical wave.
  • FIG. 11A relates to adipocytes 240 that are substantially shaped as prolate spheroids having a longitudinal axis 242, though it is appreciated that the adipocytes 240 may have other shapes including oblate spheroids, or non-spheroid shapes.
  • a cell membrane 244 of a given adipocyte 240 is subjected to the most damage/injury if the orientation of the adipocyte 240 relative to the propagation axis 270 is such that an "elongated" surface of the cell membrane 244 is substantially perpendicular to the propagation axis 270 of the transverse wave.
  • FIG. 11B shows (see 292) that in many clinical situations the adipocytes are not aligned but rather adopt many different orientations (see 294).
  • transverse mechanical waves with many different propagation axis 270 orientations (i.e., "scatter" the waves) rather than (a) delivering mechanical waves in substantially a single direction so that all propagation axes 270 of transverse mechanical waves delivered at a given time are substantially parallel to each other, or (b) focusing the waves.
  • Scattering the transverse waves may be useful for maximizing the likelihood that a given adipocyte receives a transverse mechanical wave from substantially the "correct" angle best-suited to inflict maximal damage to the cell membrane. Because the "correct" angle may be one of many different angles, the chance of achieving this correct angle increases if mechanical waves are delivered at a given time so that propagation axes are at various orientations.
  • FIG 13A One exemplary technique for accomplishing this is illustrated in FIG 13A .
  • a sonotrode having a convex rather than a flat surface it is possible to scatter the delivered transverse mechanical waves to a certain extent into biological tissue 200.
  • an energy delivery surface 180 that includes a plurality of discontinuous surfaces and/or a plurality of protrusions (see for example, concentric circular ridges 182). This may be useful for facilitating scattering of the transverse mechanical waves into the tissue (for example, compare FIG. 12 with FIG. 13A ).
  • FIG. 13B illustrates a distribution of propagation axes of transverse mechanical waves delivered at a given time.
  • energy of mechanical transverse waves of ultrasound frequency is delivered from the energy delivery surface 180 such that, at a given time:
  • theta 30 degrees.
  • the penetration depth (i.e., the depth beneath the skin surface at which the intensity of the delivered wave is reduced by a factor of e (approximately 2.718)) of the transverse wave is greater than the penetration depth of the longitudinal wave.
  • the penetration depth of the transverse ultrasound waves (for the same energy) may be, for example, at least a factor of 2 or 3 greater than that of longitudinal waves during implementation of the invention. In one non-limiting example where the frequency of the longitudinal wave mode is 61 kHz, this penetration depth is 5-10 mm for the longitudinal wave and 20-40 mm for the transverse mechanical wave.
  • the penetration depth of the longitudinal ultrasound wave is less than 1 cm, and the penetration depth of the transverse ultrasound wave is between 2 cm and 5 cm.
  • FIG. 14 It is also evident from FIG. 14 that the intensity of the longitudinal wave at the skin surface may exceed the intensity of the transverse ultrasound wave (though FIG. 14 is not necessarily intended to be to-scale).
  • ultrasound energy i.e., either longitudinal or transverse mechanical waves of ultrasound frequency
  • a first fraction of the mechanical energy delivered from energy delivery surface 180 is reflected back from the surface of biological tissue 200 and a second fraction of the mechanical energy delivered from energy delivery surface 180 is actually transmitted into biological tissue 200.
  • impedance matching techniques for example, applying petroleum jelly to energy delivery surface 180
  • the second fraction i.e. the fraction that is actually transmitted into the tissue
  • the transverse wave is not refracted as much as the longitudinal wave. This occurs because transverse waves travel slower than longitudinal waves. Therefore, the velocity difference between the incident wave and refracted transverse wave is not as great as it is between the incident and refracted longitudinal waves. Therefore, the shear wave can penetrate "deeper" because of lower refractions.
  • (i) 40-80 watts of mechanical waves of ultrasound frequency are delivered from energy delivery surface 180 ("input" power from the sonotrode 140); (ii) when in "hot” mode, 50% of the input power is absorbed by the tissue 200, while the other 50% is reflected back from the skin surface); (iii) when in "cold” mode, only 25% of the input power is absorbed by the tissue 200 while 75% of the input power is reflected.
  • transverse mechanical wave energy is absorbed in this non-limiting example (thereby providing only weak mechanical waves in the tissue 200)
  • this is sufficient to provide effective fat treatment because there is no requirement to rupture adipocytes, only to "gently" damage (or deform) the adipocytes to trigger delayed cell death of adipocytes.
  • sonotrode 140 may be characterized by multiple resonant frequencies.
  • sonotrode 140 adopts the first mode (i.e., cold mode) described in FIGS.
  • sonotrode 140 adopts the second mode (i.e., the hot mode) described in FIGS. 7B , 16 and 17B , where the vibrations in the distal portion 170 resonator are primarily in a direction substantially parallel to elongate neck axis (which happens to coincide with longitudinal axis 164) and where a longitudinal mechanical standing wave is generated in distal portion 170.
  • resonant frequency values depicted in FIG. 15A are illustrative only and may be appropriate for the system of FIGS. 7A-7C where the applicator is constructed of aluminum. In other situations, the values may differ from those depicted in FIG. 15A . Furthermore, it will be appreciated that there is no requirement of only a single cold mode resonant frequency and only a single hot mode resonant frequency as depicted in FIG. 15A . Indeed, in some embodiments, there are multiple hot and/or cold resonant frequencies (not shown in the figure).
  • FIG. 15B illustrates, for the same example depicted in FIG. 15A , the effect of the biological tissue load upon the Q-factor of the sonotrode 140 "resonator.”
  • cold mode curve is practically independent of load (human tissue) coupling and is substantially the same with and without the load.
  • the hot mode provides quite different results - i.e. the lower curve is when the biological load is contacted to sonotrode 140 and the higher curve is when no biological load is in contact with sonotrode 140. It is thus clear that the contacting decreases the Q-factor of the resonator because of energy losses to the biological tissue.
  • FIG. 16 is a flow chart of an exemplary routine for operating sonotrode 140 in hot mode.
  • step S311 B ultrasound waves having a second driving frequency (for example, a hot mode resonant frequency illustrated in FIG. 12 - this "second" driving frequency is in contrast with the "first" driving frequency of step S311A of FIG. 8 ) are generated, by ultrasound transducer 130. These ultrasound waves propagate downwards in the direction of the distal portion of the sonotrode and enter the neck portion 160 in step S315.
  • the longitudinal waves drive or induce within distal portion 170 a longitudinal standing wave on energy delivery surface 180. It is this longitudinal standing wave of the surface that, in turn, induces longitudinal waves in biological tissue 200 during treatment.
  • the path of HF and ultrasonic energy is as follows (in consecutive order): (i) HF-generator; (ii) ultrasound transducer 130; (iii) proximal portion 150 of sonotrode 140; (iv) neck portion 150 of sonotrode 140; (v) distal portion 170 of sonotrode 140; (vi) contactable energy delivery surface 180 of distal portion 170; (vii) acoustic impedance matching material between distal portion 170 and an upper surface (i.e., a skin surface) of biological tissue 200 (e.g., plastic, Teflon®, petroleum jelly, or the like); (viii) epidermis 210; (ix) dermis 220; (x) subcutaneous layers 230; (xi a) adipocyte cell membranes 244 of adipocytes 240 of the adipose tissue 230 for transverse mechanical waves; or (xi b) liquid content of adipocytes (e.g., semi-
  • FIG. 17A is a flow chart of an exemplary technique for operating ultrasound apparatus 100 including sonotrode 140 in cold mode.
  • step S51 high frequency electrical current is generated by current source 110.
  • energy of the electrical current is converted (for example, by ultrasound transducer 130) to ultrasound energy - for example, ultrasound energy whose frequency matches the driving frequency of the cold mode (in the example of FIG. 12 , about 69 kHz).
  • ultrasound waves propagate within sonotrode 140 (for example, in a longitudinal direction in proximal 150 and neck 160 portions towards distal portion 170) and induce vibrations of the distal portion 170 resonator.
  • step S523 standing transverse mechanical waves of an ultrasound frequency resonate in a direction substantially perpendicular to an elongate axis of neck portion 160 and to the longitudinal axis 164 causing the delivery of transverse mechanical waves of ultrasound frequency from energy delivery surface 180.
  • step S527 the transverse mechanical waves propagate through an impedance matching material (e.g., petroleum jelly).
  • this transverse mechanical wave propagates through the dermis and epidermis layers to reach the subcutaneous layers.
  • step S535 the transverse mechanical wave propagates through the adipose tissue beneath the dermis.
  • the transverse mechanical wave propagates through fibers and/or cell membranes to damage, injure, and/or deform the cell membranes, which ultimately triggers a biological process of delayed cell death.
  • FIG. 17B is a flow chart of an exemplary technique for operating ultrasound apparatus 100 including sonotrode 140 in hot mode.
  • step S411 high frequency electrical current is generated by current source 110.
  • step S415 energy of the electrical current is converted (for example, by ultrasound transducer 130) to ultrasound energy - for example, ultrasound energy whose frequency matches the driving frequency of the hot mode (in the example of FIG. 12 , about 59 kHz).
  • ultrasound waves propagate within sonotrode 140 (for example, in a longitudinal direction in proximal 150 and neck 160 portions towards distal portion 170) and induce vibrations of the distal portion 170 resonator.
  • standing transverse mechanical waves of an ultrasound frequency resonate in a direction substantially parallel to an elongate axis of neck portion 160 and to the longitudinal axis 164 causing the delivery of longitudinal mechanical waves of an ultrasound frequency from energy delivery surface 180.
  • the transverse mechanical waves propagates through an impedance matching material (e.g., petroleum jelly).
  • this longitudinal mechanical wave propagates through the dermis and epidermis layers to reach the subcutaneous layers.
  • the longitudinal wave propagates through adipose tissue beneath the dermis.
  • the longitudinal mechanical wave may propagate through a liquid fraction (e.g., semi-liquid triglycerides) of adipocytes to heat the adipose tissue.
  • the dermis and/or epidermis are also heated by the longitudinal ultrasound waves.
  • this is accomplished by operating ultrasound apparatus 100 in "hot mode" (see FIG. 18 ).
  • another form of energy may be provided to heat upper layers of tissue (for example, RF energy - see FIG. 19 ).
  • FIG. 18 is a flow chart of a cyclical hybrid treatment technique provided in accordance with some embodiments.
  • step S201 sonotrode 140 is brought into contact (or proximity) with the skin surface.
  • step S201 is depicted as occurring before step S205, this is not a limitation, and other orders are contemplated and may be used.
  • a preliminary or first treatment stage is carried out wherein longitudinal ultrasound energy is delivered via energy delivery surface 180 to heat the biological tissue for a period of time t hot (e.g., between 2 and 10 seconds, or between 4 and 6 seconds).
  • the mechanical wave energy of an ultrasound frequency delivered during step S205 is primarily longitudinal wave energy (i.e., at least 50%, 70%, or 90% longitudinal mechanical wave energy).
  • step 205 is operative to heat a 'control' region of the dermis and/or of the epidermis (for example, having a thickness of at least 0.5 cm and an area of at least 5 cm 2 for a total volume of 2.5 cm 3 ) to a temperature that is at least about 42 degrees Celsius (or at least 45 degrees) for a period of time that is at least about 2 seconds, or at least 4 seconds or at least 8 seconds.
  • a 'control' region of the dermis and/or of the epidermis for example, having a thickness of at least 0.5 cm and an area of at least 5 cm 2 for a total volume of 2.5 cm 3 ) to a temperature that is at least about 42 degrees Celsius (or at least 45 degrees) for a period of time that is at least about 2 seconds, or at least 4 seconds or at least 8 seconds.
  • epidermal cooling is used during the hot mode pre-heating phase of step S205 and/or main phase of step S209, in order to reduce pain and to prevent sonotrode 140 from "overheating" (for example, heating above 50 degrees Celsius or 60 degrees Celsius or 70 degrees Celsius or any other 'undesirable' temperature).
  • Any technique for cooling a sonotrode known in the art may be used - for example, cooling with a liquid such as water.
  • the power flux of the delivered longitudinal ultrasound wave energy which is delivered from applicator 140 is at least about 3, 5, 7, or 10 watts/cm 2 .
  • this power flux it at most about 35, 25, or 20 watts/cm 2 .
  • the delivered ultrasound waves comprise, at least 90% (or at least 70% or at least 50%) longitudinal ultrasound waves.
  • a main treatment phase is carried out wherein mechanical waves of ultrasound frequency are delivered to the biological tissue 200 via energy delivery surface 180 for a period of time t COLD (e.g., between 10 and 30 seconds, or between 15 and 25 seconds). At least about 30%, 50%, 70%, or 90% of the energy of the mechanical waves of ultrasound frequency are transverse wave energy for at least 90% or at least 70% or at least 50% of the time t COLD of step S209.
  • t COLD e.g., between 10 and 30 seconds, or between 15 and 25 seconds.
  • a power level of delivered mechanical waves of an ultrasound frequency (i.e. delivered to the biological tissue via energy delivery surface 180) during step S209 is at least 20% or at least 30% or at least 50% a power level of delivered mechanical waves of an ultrasound frequency (i.e. delivered to the biological tissue via energy delivery surface 180) during step S205.
  • At least a portion of the dermis (for example, having a thickness of at least 0.5 cm and an area of at least 5 cm 2 for a total volume of 2.5 cm 3 ) is allowed to cool by at least about 1 or 2 degrees Celsius as transverse mechanical wave energy is delivered to biological tissue 200.
  • the power flux of the delivered transverse ultrasound wave energy which is delivered from applicator 140 during the step S205 is at least about 3, 5, 7, or 10 watts/cm 2 .
  • this power flux it at most 35 watts/cm 2 or at most 25 watts/cm 2 or at most 20 watts/cm 2 .
  • a ratio of the average power flux during step S205 and step S209 is at least about 0.3, 0.5, 0.7, or 0.9.
  • a ratio of the average power flux during step S205 and step S209 is at most about 3, 2, or 1.5.
  • the average power flux delivered from sonotrode 140 during step S205 is substantially equal (i.e., within a tolerance of, for example, about 50%, 30%, 10%, 5%, or 1 %) to the average power flux delivered from sonotrode 140 during step S209. Nevertheless, because the longitudinal energy of step S205 is better absorbed than the transverse energy of step S209 for which a greater fraction is reflected from biological tissue, in these embodiments, more energy may be absorbed by biological tissue 200 during step S205.
  • steps S205 and S209 may be repeated any number of times in order, such as, for example, at least about 5 times or 10 times.
  • the ratio between t COLD and t HOT is at least 2:1 or at least 2.5:1. In some embodiments, the ratio between t COLD and t HOT is at most 5:1 or at most 3.5:1.
  • the ratio between T COLD and t HOT is about 3:1.
  • mechanical waves of ultrasound frequency are delivered from sonotrode 140 at during the time that sonotrode 140 is in transverse motion over the surface of the biological tissue.
  • the recommended total treatment time for all cycles is between about 0.25 min/cm 2 and 0.45 min/cm 2 of tissue treated.
  • 100 cm 2 is treated, and the minimum recommended time of treatment is 25 minutes, and the maximum recommended time of treatment is 45 minutes.
  • each treatment cycle is 20 seconds (e.g., 5 seconds of cold mode and 15 seconds of hot mode), between 75 and 135 treatment cycles is preferred.
  • the cold mode of step S209 is provided by causing transducer 130 to operate at a first "driving frequency" associated with the "cold mode” resonant frequency (see FIGS. 15A-15B ), and the hot mode of step S205 is provided by causing transducer 130 to operate at a second "driving frequency” associated with the "hot mode” resonant frequency.
  • a difference between the first and second driving frequencies is at least 3 kHz.
  • a ratio between (i) the difference between the first and second driving frequencies; and (ii) a maximum of the first and second driving frequencies is at least 0.1.
  • the device controller 120 is operative to cause the sonotrode 140 and the ultrasound transducer 130 to: A) effect (i.e., in step S205) a preliminary phase of a duration having a duration t HOT that is at least 10 seconds and at most 30 seconds where the sonotrode 140 and the ultrasound transducer 130 provide the longitudinal wave mode; and B) after the preliminary phase, effect (i.e., in step S209) a main phase having a duration t COLD that is at least twice the duration t HOT of the preliminary phase where the sonotrode 140 and the ultrasound transducer 130 provide the transverse wave mode.
  • the controller 120 is operative to repeat the preliminary and the main phases at least 10 times.
  • the controller 120 is operative to commence the main phase of step S209 within 15 seconds of a completion of the preliminary phase of step S205.
  • the controller 120 is operative such that a ratio between the duration t COLD of the main phase and the duration t HOT of the preliminary phase is at most 5.
  • RF energy is delivered to the biological tissue 200 to pre-heat the biological tissue during the preliminary phase.
  • FIG. 20A is a cross-section image of sonotrode 140 including a plurality of protrusions or ridges 182
  • FIG. 20B illustrates the concentric ridges 182 located on energy delivery surface 180. As shown in FIG. 20B , the ridges are "denser" towards the center of energy delivery surface. Also, it is noted that in some embodiments, the positions of the concentric ridges 182 may coincide with the position of the nodes or anti-nodes of the ultrasound waves delivered via energy delivery surface (i.e. either longitudinal or transverse ultrasound waves).
  • a distance between adjacent concentric ridges 182 may be an integral multiple (or a reciprocal of an integral multiple) of node DIST a distance between adjacent nodes or anti-nodes ( FIGS. 7A-B ), in either the "hot mode” or the "cold mode” (i.e., a multiple of ( node DIST ) traverse and/or ( node DIST ) longitudinal ) .
  • FIG. 21 illustrates electric circuitry for supplying a regulated electrical current to ultrasound transducer 130.
  • the electrical circuitry of FIG. 21 may include the following elements: 904 - internal capacitance of the ultrasonic transducer; 912 - resonant RF-inductor (which together with element 904 comprises the in-series resonance circuit); 903 - HF-generator supplying transducer 904, for example, the generator may be an E-class switching module based on the Mosfet transistor; 901 - DC-power supply; 911 - DC-current sensor (serving for DC-current resonance control; 910 - HF-voltage sensor (serving for control of resonance at LC-circuit (912/904); 913 - ultrasonic energy sensors; 905 - system controller (microprocessor based); 902 - HF-driver of the generator 903.
  • 904 - internal capacitance of the ultrasonic transducer 912 - resonant RF-inductor (which together with element
  • FIG. 22 is an illustration of a system for determining 'hot mode' and 'cold mode' 'driving' resonant frequencies for "calibration" of apparatus 100.
  • the system of FIG. 22 includes biological tissue (for example, pig flesh) to which ultrasound energy is delivered.
  • thermocouple 605 which is operatively linked to display 620.
  • thermocouple 605 When the apparatus 100 is in "hot mode" most of the energy is dissipated at relatively “shallow depths" of the biological tissue. Thus, when energy meter 620 indicates a 'maximum voltage' across thermocouple 605, this is indicative that apparatus 100 is operating at a "hot mode” driving frequency. This information about the driving frequency may be saved for later use.
  • the ultrasound energy is "deeper penetrating" and this is detected by receiving transducer 630 which is operatively linked to energy meter 610.
  • energy meter 610 indicates a 'maximum voltage' across receiving transducer 630, this is indicative that apparatus 100 is operating at a "cold mode" driving frequency. This information about the driving frequency may be saved for later use.
  • FIG. 23 is a flow chart of an exemplary frequency-tuning routine to "search" for a "best” operating frequency. In some embodiments, one or more steps of the routine of FIG. 23 are carried out automatically at least in part by controller 120.
  • the frequency tuning is used in order to locate a "hot mode” or “cold mode” resonance frequency of sonotrode 140.
  • transducer 130 is operated at a plurality of "candidate frequencies.” For each candidate frequency, a respective indication of a power of ultrasound waves produced by ultrasound transducer 130 is determined. It may be assumed that the candidate frequency associated with a "local maximum" of ultrasound wave power (i.e. local maximum with respect to frequency) is closest to the resonance frequency (i.e., hot mode or cold mode resonance frequency). Thus, in accordance with the power indications, an operating frequency of transducer 130 may then be selected.
  • the indication of the power of ultrasound waves produced by ultrasound transducer 130 may be a power consumption (or current consumption) of ultrasound transducer 130.
  • a greater power consumption or current consumption of ultrasound transducer 130 may be indicative of a greater power of ultrasound waves produced by ultrasound transducer 130.
  • apparatus 100 may include a meter (for example, a current meter) for measuring an indication of current consumption by ultrasound transducer 130.
  • one or more "measuring transducers” may be associated with sonotrode 140 to measure an intensity of ultrasound vibrations or waves propagating within sonotrode 140.
  • step S855 the ultrasound transducer is operated at the selected "candidate frequency.”
  • steps s851 and S855 may be repeated a number of times (for example, at least about 5 times or at least about 10 times or at least about 20 times within a given time period - for example, within 2 minutes or within 1 minute or within 30 seconds or within 15 seconds).
  • the resonant frequency (either for hot mode or cold mode) may "drift" or change over time, and thus, repeating steps S851 and S855 over time may be useful for periodically "re-tuning" apparatus 100.
  • device controller 120 is configured to: i) effect a frequency scan by operating the ultrasound transducer 130 at a plurality of different candidate frequencies and determining, for each given candidate frequency of the plurality of frequencies, a respective indication of a power of ultrasound waves generated by the ultrasound transducer 130 that is associated with the given candidate frequency; ii) in accordance with the power indications, select an operating frequency from the plurality of candidate frequencies; and iii) operate the transducer 130 at the selected frequency for at least 10 seconds.
  • efficiency of conversion of electrical power to acoustic power is 40-50% approximately.
  • taking into account the efficiency of HF-power source 80-90%, then around 40-80 watts of acoustic power are provided.
  • irradiative surface of sonotrode is ⁇ 6 cm 2 approximately. Therefore the energy flux from the acoustic irradiative surface is 7-13 watts/cm 2 .
  • apparatus 100 may operate in "hummer mode" where a plurality of pulses of ultrasound energy are delivered using sonotrode 140. In some embodiments, this may be carried by delivering a current pulses to transducer 130.
  • device controller 120 which regulates current provided to transducer 130, is configured as a pulse generator (or is operatively linked to a pulse generator), and may provide a current having a profile similar to the profile illustrated in FIG. 24 .
  • current (and hence ultrasound energy) is provided as a series of relatively “short” enforced ultrasonic pulses. This may be useful, for example, for drug delivery technology.
  • the frequency of modulation can be between 1 Hz and 100 Hz.
  • a ratio between a pulse width and the "distance between pulses" is at most 0.5, or at most 0.3, or at most 0.1 or at most 0.05.
  • a ratio between a peak power of transducer 130 and an average power of transducer 130 is at least 1.5, or at least 3, or at least 5, or at least 10.
  • the pulse generator is operative to establish a value of said duty cycle parameter that is between 1% and 100%.
  • the pulse generator is operative to establish a value of said duty cycle parameter that is between 15% and 30%.
  • the pulse generator is operative to establish a rectangular pulse shape.
  • a current source 110 provides electrical current to transducer 130
  • device controller 120 is operative to cause the electromagnetic energy source to deliver said output electromagnetic signal as a pulsed signal having one or more pulse parameters, said pulse controller operative to effect a pulse-width modulation of the electrical current provided to transducer 130.
  • At least one pulse parameter is selected from the group consisting of an amplitude, pulse duration, a pulse shape, a duty cycle parameter, a pulse sequence parameter, a pulse rise-time, and a pulse frequency.
  • FIG. 25A-25B illustrates an example adipocyte which has been subjected to ultrasound waves in accordance with some embodiments of the present invention.
  • adipocyte of FIGS. 25A-25B One feature of the adipocyte of FIGS. 25A-25B is that undulating membrane geometry has been introduced to the adipocyte.
  • the ultrasound energy may do this on a relatively "large scale” and introduce undulating membrane geometry in at least 30% (or at least 10% or at least 50%) of the adipocytes within the control volume of FIG. 10 .
  • introduction of the undulating membrane geometry deformation increases membrane surface area by at least 20% without increasing adipocyte volume by more than 5%. (for example, see “Face 1" in FIG. 25B ).
  • introducing of the undulating membrane geometry increases, by at least 50%, a surface area of a contiguous cell membrane portion whose mass is 15% of a total cell membrane mass.
  • the surface area of a "subportion" of the cell membrane i.e. see Face 1 may increase by at least 50%.
  • each of the verbs, "comprise” “include” and “have”, and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of members, components, elements or parts of the subject or subjects of the verb.
  • an element means one element or more than one element.

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  • Radiology & Medical Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Thermotherapy And Cooling Therapy Devices (AREA)

Claims (14)

  1. Appareil pour traiter un tissu biologique, comprenant :
    un transducteur à ultrasons (130) configuré pour produire de l'énergie à ultrasons ;
    et
    un applicateur à ultrasons (140) connecté au transducteur à ultrasons et comprenant une surface de distribution d'énergie (180),
    caractérisé en ce que
    l'applicateur est formé de manière à avoir une première fréquence de résonance dont la surface de distribution d'énergie (180) de l'applicateur vibre parallèlement à la direction de propagation des ultrasons à travers l'applicateur et une seconde fréquence de résonance différente dans laquelle la surface de distribution d'énergie (180) de l'applicateur vibre dans le plan normal à la direction de propagation des ultrasons à travers l'applicateur, et
    le dispositif comporte un mode longitudinal de fonctionnement dans lequel le transducteur à ultrasons excite l'applicateur à ladite première fréquence et un mode transversal de fonctionnement dans lequel le transducteur à ultrasons excite l'applicateur au niveau de ladite deuxième fréquence.
  2. Appareil selon la revendication 1, dans lequel l'énergie à ultrasons émise par la surface de distribution de l'énergie lors du fonctionnement en mode transversal se propage dans des directions qui sont inclinées mutuellement, de sorte que l'énergie à ultrasons des ondes à ultrasons transversales soit incidente à partir de plusieurs directions sur des points se trouvant sur le trajet de l'énergie à ultrasons émise par l'applicateur.
  3. Appareil selon la revendication 2, dans lequel la surface de distribution d'énergie de l'applicateur a des propriétés de surface telles que les ondes à ultrasons délivrées ont les propriétés suivantes :
    i) au moins 30 % de l'énergie des ondes transversales mécaniques induites de la surface de distribution d'énergie a une direction de propagation (270) dans les 30 degrés d'une direction donnée (164) ; et
    ii) au moins 30 % de l'énergie des ondes mécaniques transversales émises a une direction de propagation (270) qui diffère de la direction donnée (164) d'au moins 30 degrés.
  4. Appareil selon la revendication 3, dans lequel la surface de distribution d'énergie (180) est une surface convexe ayant sur celle-ci situé au moins l'un des éléments parmi :
    i) plusieurs surfaces discontinues.
    ii) plusieurs saillies ;
    iii) plusieurs indentations ;
    iv) plusieurs nervures verticales, et
    v) plusieurs nervures circulaires concentriques,
    de sorte que la dispersion des ondes à ultrasons transversales émises par la surface de distribution d'énergie soit facilitée.
  5. Appareil selon l'une quelconque des précédentes revendications, dans lequel, dans le mode transversal de fonctionnement au moins 30 %, plus préférablement au moins 70 % de l'énergie de l'onde à ultrasons émise par la surface de distribution d'énergie est une énergie d'onde à ultrasons transversale.
  6. Appareil selon l'une quelconque des précédentes revendications, dans lequel, dans le mode longitudinal de fonctionnement au moins 30 %, plus préférablement au moins 70 % de l'énergie de l'onde à ultrasons émise par la surface de distribution d'énergie est une énergie d'onde à ultrasons longitudinale.
  7. Appareil selon l'une quelconque des précédentes revendications, comprenant en outre un contrôleur (120) configuré pour :
    i) effectuer un balayage de fréquence en actionnant le transducteur à ultrasons (130) à plusieurs fréquences candidates différentes et en déterminant, pour chaque fréquence candidate donnée des diverses fréquences, une indication respective d'une puissance des ondes à ultrasons produites par le transducteur à ultrasons (130) qui est associée à la fréquence candidate donnée ;
    ii) en fonction des indications de puissance, sélectionner une fréquence de fonctionnement à partir de plusieurs fréquences candidates, et
    iii) actionner le transducteur (130) à la fréquence sélectionnée pendant au moins 10 secondes.
  8. Appareil selon l'une quelconque des revendications précédentes, comprenant en outre un contrôleur (120) fonctionnant pour mener le transducteur à ultrasons (130) à :
    i) effectuer une phase préliminaire d'une durée d'une durée tCHAUD qui est à au moins 10 secondes et d'au plus 30 secondes, où l'applicateur (140) et le transducteur à ultrasons (130) fonctionnent dans le mode à onde longitudinale ; et
    ii) après la phase préliminaire, effectuer une phase principale ayant une durée tFROID qui est au moins le double de la durée tCHAUD de la phase préliminaire, où l'applicateur (140) et le transducteur à ultrasons (130) fonctionnent dans le mode d'onde transversale.
  9. Appareil selon la revendication 8, dans lequel le contrôleur (120) est capable d'effectuer au moins l'une des opérations suivantes, à savoir :
    (i) commencer la phase principale dans les 15 secondes suivant la fin de la phase préliminaire ;
    ii) répéter les phases préliminaires et principales au moins 10 fois ;
    et
    iii) régler la durée tFROID de la phase principale pour ne pas dépasser cinq fois la durée tCHAUD de la phase préliminaire.
  10. Appareil selon l'une quelconque des précédentes revendications, dans lequel l'applicateur comprend une partie proximale (150) couplée de manière opérationnelle au transducteur à ultrasons (130), une partie distale (170) définissant la surface de distribution d'énergie (180), et une partie de col allongée (160) reliant la partie proximale (150) à la partie distale (170), l'applicateur étant dimensionné de telle sorte que :
    (i) le rapport entre la longueur (B) de la partie de col (160) mesurée parallèlement à un axe allongé de la partie de col et de la largeur (d1) de la partie du col (160) mesurée perpendiculairement à l'axe allongé du col est d'au moins 1,5 : 1 ;
    (ii) le rapport entre la largeur (d2) de la partie distale (170) mesurée perpendiculairement à l'axe allongé de la partie de col et la longueur (C) de la partie distale (170) mesurée parallèlement à l'axe allongé de la partie de col (160) est d'au moins 2 : 1 ;
    (iii) le rapport entre la largeur (D) de la partie proximale (150) mesurée perpendiculairement à l'axe allongé de la partie de col (160) et la largeur (d1) de la partie de col (160) est d'au moins 2,5 : 1, et
    (iv) le rapport entre la largeur (d2) de la partie distale (170) et la largeur (d1) de la partie de col (160) est d'au moins 2 : 1.
  11. Appareil selon la revendication 10, dans lequel le transducteur à ultrasons (130) et la sonotrode (140) sont configurés de telle sorte que le transducteur à ultrasons induit des vibrations mécaniques dans au moins l'une de la partie proximale (150) et de la partie de col (160) de telle sorte que :
    i) ces dernières vibrations mécaniques se trouvent dans une direction qui est sensiblement parallèle, dans une tolérance de 20 degrés, à l'axe du col allongé, et
    ii) les vibrations mécaniques induisent en outre les vibrations de la surface de distribution d'énergie dans le plan transversal dans la direction de propagation de l'énergie des ultrasons.
  12. Appareil selon l'une quelconque des revendications précédentes, dans lequel l'impédance acoustique d'au moins une partie de l'applicateur (140) est d'au moins 5 MRayl.
  13. Appareil selon l'une quelconque des précédentes revendications, dans lequel l'énergie d'alimentation du transducteur à ultrasons (130) est modulée en largeur d'impulsion.
  14. Appareil selon l'une quelconque des précédentes revendications, dans lequel le transducteur à ultrasons (130) et l'applicateur (140) sont configurés pour fournir un flux d'énergie par l'intermédiaire de la surface de distribution d'énergie (180) qui est au moins 7 watts/cm2.
EP09705080.1A 2008-02-01 2009-02-01 Appareil pour dégradation sélective d'adipocytes par ultrason Active EP2252369B1 (fr)

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US6335508P 2008-02-01 2008-02-01
US10073708P 2008-09-28 2008-09-28
PCT/IB2009/050391 WO2009095894A2 (fr) 2008-02-01 2009-02-01 Appareil et procédé pour dégradation sélective d’adipocytes par ultrason

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CA2713939A1 (fr) 2009-08-06
CA2713939C (fr) 2017-12-05
WO2009095894A2 (fr) 2009-08-06
IL207343A0 (en) 2010-12-30
IL207343A (en) 2016-09-29
US20140142469A1 (en) 2014-05-22
EP2252369A2 (fr) 2010-11-24
WO2009095894A3 (fr) 2009-12-30
US20110213279A1 (en) 2011-09-01
US8579835B2 (en) 2013-11-12

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